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Unravelling Pathobiological Molecular Mechanisms of T-Cell Acute Lymphoblastic Leukemia

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Unravelling Pathobiological Molecular Mechanisms of T-Cell Acute Lymphoblastic Leukemia Unravelling Pathobiological Molecular Mechanisms of T-Cell Acute Lymphoblastic Leukemia Rui D. Mendes 1 Unravelling Pathobiological Molecular Mechanisms of T-Cell Acute Lymphoblastic Leukemia Rui D. Mendes 2 The research here described was conducted in the department of Pediatric Oncology/ Hematology at Erasmus Medical Center - Sophia Children’s Hospital, Rotterdam, the Netherlands. The studies described in this thesis were financially supported by Stichting Kinderen Kankervrij (KiKa). Publication of this thesis was financially supported by: Cover: Nathan Sawaya. The original picture displays a two metre sculpture named ‘Building Bricks of Life’ made by the artist Nathan Sawaya. “Just as each brick plays an important part in holding the sculpture together, each gene within the human genome helps us understand more about ourselves as humans and how we are all connected” - Nathan Sawaya Book design: Rui D. Mendes Printed by: ISBN: XXX-XX-XXXX-XXX-X Copyright © 2016 by Rui D. Mendes. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without prior permission of the author. 3 Unravelling Pathobiological Molecular Mechanisms of T-Cell Acute Lymphoblastic Leukemia Het ontrafelen van pathobiologische moleculaire mechanismes in T-cel acute lymphoblastische leukemie Thesis to obtain the degree of doctor from Erasmus University Rotterdam by command of the rector magnificus Prof.dr. H.A.P. Pols and in accordance with the decision of the Doctorate Board. The public defence shall be held on Tuesday December 13, 2016 at 13:30 hours by Rui Daniel Martins Nunes Mendes born in Lisbon, Portugal 4 Doctoral Committee: Promotor: Prof.dr. R. Pieters Leescommissie: Prof.dr. C.M. Zwaan Prof.dr. F.J. Staal Prof.dr. F.G. Grosveld Copromotor: Dr. J.P.P. Meijerink 5 To my beloved ones: Mariana, Joaquim e André, and in memory of my cousin João Martins. 6 Contents Chapter 1 General Introduction & Aims of the Thesis 9 Chapter 2 The relevance of PTEN-AKT in relation to 30 NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia Haematologica. 2016 Sep;101(9):1010-7 Chapter 3 PTEN microdeletions in T-cell acute lymphoblastic 49 leukemia are caused by illegitimate RAG-mediated recombination events. Blood, 2014, 124(4):567-78 Chapter 4 Lentiviral gene transfer into human and murine 77 hematopoietic stem cells: size matters BMC Res Notes. 2016 Jun 16;9:312 Chapter 5 Downregulation of CD44 functionally defines human 88 T-cell lineage commitment Manuscript submitted Chapter 6 T-Cell Acute Lymphoblastic Leukemia Oncogenes 113 hijack T-Cell Developmental Programs for Leukemogenesis: the arrest of Early T-cell programs by MEF2C, LYL1 or LMO2 Manuscript in preparation Chapter 7 General discussion & Future perspectives 135 Chapter 8 Summary/ Samenvatting 145 Supplementary data 151 Curriculum Vitae 181 List of Publications 182 Portfolio 183 Acknowledgements 184 7 8 Chapter 1 General Introduction & Aims of the Thesis 9 1. General introduction 1.1. Hematopoiesis and leukemia Daily, each person produces approximately 1011–1012 blood cells to maintain the number of cells in the peripheral circulation.[1] The continuous production of mature blood cells is essential as these cells have a limited lifespan. This renewal process is supported by hematopoietic stem cells (HSC) that are located in the medulla of the bone (bone marrow), especially in the pelvis, femur, and sternum. Although in smaller numbers, they can also be found in umbilical cord blood (UCB) and in peripheral blood. HSCs give rise to all types of mature blood cells (Figure 1) and have the capacity of self-renewal, since upon cellular division some of the daughter cells remain as HSCs.[2] Instead, the other daughters of HSCs differentiate into myeloid and lymphoid progenitor cells that further give rise to the development of all blood cell types. These changes can often be tracked by monitoring the presence of proteins on the surface of the cell, usually determined as Cluster of Differentiation (CD) markers. HSCs express CD34 and lack markers that are lineage-specific, such as the expression of CD3 in T-cells, CD19 in B-cells, CD33 in myeloid and CD56 in NK-lineage cells. The process of maturation from HSC to effector blood cells occurs in the bone marrow and/or secondary lymphoid organs, including thymus and spleen. Following specific stimuli, such as growth factors, chemokines and contact with cells present in different microenvironments, the hematopoietic precursor cell undergoes changes in chromatin organization and gene expression that promote the differentiation of the cell towards a specific cell type, limiting the potential for differentiation into alternative lineages. [2] However, during the process of maturation, the blood precursor cells may acquire mutations, chromosomal rearrangements and epigenetic changes that prompt the cells to uncontrollable proliferation called leukemia.[3] As leukemic cells continue to grow and divide, they eventually outcompete the normal blood cells, which results in defective protection against infections and pathogens, and hemorrhages.[4] Clinically and pathologically, leukemias can be classified in four main categories. The first division is between acute and chronic leukemias. Acute leukemias are the most common forms of leukemia in children, which are characterized by a rapid increase in the number of leukemic cells.[5] Immediate treatment is required due to the rapid progression and accumulation of malignant cells that are released into the bloodstream and spread to other organs. Other symptoms can be manifested according to the tissue occupied; infiltration of the lymph nodes causes lymphadenopathy and infiltration of the central nervous system may provoke headaches. Chronic leukemia is characterized by the excessive 10 accumulation of relatively more mature leukemic cells, and typically it takes months or years to progress. Chronic leukemia mostly occurs in adults. In addition, leukemias can be classified into myeloid or lymphoblastic leukemia, according to the blood lineage of the affected cell. Furthermore, lymphoblastic leukemias can be further divided into B-cell or T-cell lymphoblastic leukemia. 1.2. Acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children, comprising approximately 25% of all childhood malignancies.[6] Almost three-fourths of childhood leukemia (ages 0-18) is ALL, while the most common form of acute leukemia in adults is acute myeloid leukemia (AML). In the majority of the cases the leukemic blasts are detected on a blood smear. Blood and bone marrow are used for further classification by immuno-phenotyping and genotyping. A lumbar puncture is performed to detect central nervous system involvement. Immunophenotypic analysis of the blasts indicates whether the leukemia is from myeloid (neutrophils, eosinophils, or basophils) or lymphoblastic origin (B- or T-lymphocytes). Genomic analysis is used to determine the underlying genetic abnormalities, which are associated with specific risks for relapse and survival.[6] Treatment protocols are based on combination chemotherapy, including different classes of drugs. Survival rates of ALL patients improved from less than 10% before 1970 to over 80%.[7] 1.3. T-cell acute lymphoblastic leukemia T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of lymphoid precursor cells residing in the thymus that are primed towards T-cell development. T- ALL represents about 15% of pediatric ALL cases and 25% of adult ALL cases,[8] and is typically more frequent in males than females. Clinically, T-ALL patients show diffuse infiltration of the bone marrow by immature T-cell blasts, high white blood cells counts, mediastinal masses with pleural effusions, and frequent infiltration of the central nervous system at diagnosis.[9] Despite the advances in our understanding of the molecular genetics of T-ALL, current treatments are mostly based on multi-agent chemotherapy and stem cell transplantation in part of the patients. Although these treatment regimens are highly effective with overall survival reaching 85% on current treatment protocols, they are often associated with severe toxicity and 11 long-term side effects such as cardiomyopathy, bone necrosis, chronic graft versus host disease, infertility or secondary malignancies, impairing the quality of adult life. In addition, about 15% of pediatric T-ALL patients still relapse due to therapy resistance and those cases are associated with very dismal survival perspectives.[5, 10] Therefore, current research efforts are focused on the search for targets that will eventually lead to more effective and less toxic antileukemic drugs. In order to achieve more specific or individualized therapies it is crucial to improve our understanding of the molecular events that lead to the disease, and the mechanisms involved in disease progression and relapse. 1.3.1. T-cell development in the thymus T-cells can be distinguished between αβ- or γδ-cells based on the composition of the T-cell antigen receptor (TCR). While αβ T-cells comprise the majority (95%) of T-cell populations in lymphoid organs, γδ T-cells only represent a small fraction of T-cells that are mainly located in the gut mucosa. Normal T-cell development is a strictly regulated, multistep process in which lymphoid precursor cells differentiate into functionally diverse T-lymphocyte subsets in the thymus microenvironment. The different
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